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Immunity. 2019 Feb 19;50(2):390-402.e10. doi: 10.1016/j.immuni.2019.01.002. Epub 2019 Jan 29.

A Neutrophil Timer Coordinates Immune Defense and Vascular Protection.

Author information

1
Area of Developmental and Cell Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
2
Area of Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
3
Unidad de Investigación Neurovascular, Department of Pharmacology, Faculty of Medicine, Universidad Complutense; Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
4
Area of Developmental and Cell Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Present address: Tisch Cancer Institute, Mount Sinai School of Medicine, New York City, New York, USA.
5
Area of Developmental and Cell Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Present address: Centro Nacional de Biotecnología, Madrid, Spain.
6
Immunology Unit, Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona.
7
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillians-Universität München; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
8
Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, Germany.
9
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, Singapore.
10
Inserm Unité Mixte de Recherche (UMR) S996, Université Paris-Sud, Laboratory of Excellence in Research on Medication and Innovative Therapeutics, Clamart, France.
11
Department of Immunology, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain.
12
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillians-Universität München.
13
Department of Clinical Pharmacology, Instituto Teófilo Hernando, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
14
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillians-Universität München; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
15
Area of Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Department of Cardiology, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, Madrid, Spain.
16
Area of Developmental and Cell Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillians-Universität München. Electronic address: ahidalgo@cnic.es.

Abstract

Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.

KEYWORDS:

Bmal1; CXCR2; CXCR4; Candida albicans; Neutrophil; circadian clock; infection; inflammation; myocardial infarction; neutrophil aging

PMID:
30709741
DOI:
10.1016/j.immuni.2019.01.002
[Indexed for MEDLINE]

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